Is TTC19 p.Met238Thr (c.713T>C) pathogenic?

TTC19 p.Met238Thr (c.713T>C) is classified Conflicting classifications of pathogenicity in TTC19 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.7261); Very rare (popmax 0.00263%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TTC19 p.Met238Thr (c.713T>C)?

TTC19 p.Met238Thr (c.713T>C) is associated with Inborn genetic diseases, mitochondrial complex III deficiency nuclear type 2 (ClinVar).

How common is TTC19 p.Met238Thr (c.713T>C) in the general population?

TTC19 p.Met238Thr (c.713T>C) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about TTC19 p.Met238Thr (c.713T>C)?

AlphaMissense predicts likely pathogenic (score 0.7261) — an in-silico prediction, not a clinical call.

TTC19 p.Met238Thr

c.713T>C · rs140719848 · VCV889258

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7261	likely pathogenic
REVEL	0.688	pathogenic-leaning
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.9 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,179,854 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00936% 151/1,613,876 alleles · very rare exomes 134/1,461,664 · genomes 17/152,212 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.341%	293
Remaining individualsnot grpmax-eligible	0.0272%	3,675
European (non-Finnish)grpmax	0.00263%	38,060
Admixed American	0.00167%	59,996
South Asian	0.0011%	91,080

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TTC19
Protein: p.Met238Thr
Coding: c.713T>C
MANE Select: NM_017775
dbSNP: rs140719848
Type: single nucleotide variant
Location: chr17:16025053 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.28

Full TTC19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: mitochondrial complex III deficiency nuclear type 2

Similar variants

TTC19 p.Gln195Ter Pathogenic/Likely pathogenic ★★ same condition
TTC19 p.Leu185Pro Pathogenic/Likely pathogenic ★★ same condition
TTC19 p.Leu219Ter Pathogenic ★★ same condition
TTC19 c.581+4A>C Uncertain significance ★★ same condition
TTC19 c.994+3A>T Uncertain significance ★★ same condition
TTC19 p.Ala122Thr Uncertain significance ★★ ⚠ same condition
TTC19 p.Ala200Val Uncertain significance ★★ ⚠ same condition
TTC19 p.Ala263Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ttc19-p-met238thr (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown