Is TKFC p.Ala375Val (c.1124C>T) pathogenic?

TKFC p.Ala375Val (c.1124C>T) is classified Likely benign in TKFC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely benign (0.0782); Ultra-rare (popmax 0.0173%, afr).

How common is TKFC p.Ala375Val (c.1124C>T) in the general population?

TKFC p.Ala375Val (c.1124C>T) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about TKFC p.Ala375Val (c.1124C>T)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

TKFC p.Ala375Val

c.1124C>T · VCV3969121

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.6	GERP -4.6
Regional constraint	o/e 0.92	unconstrained · MANE · 12 kb · p 0.025 · regional, not allelic
Overall
CADD	0.685	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 0.0173% African / African-American · 13/75,006 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00812%

Overall 0.00217% 35/1,612,322 alleles · ultra-rare exomes 26/1,460,016 · genomes 9/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,770
South Asian	0.0143%	7,000
Remaining individualsnot grpmax-eligible	0.0016%	62,364
European (non-Finnish)	0.000678%	147,501

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: TKFC
Protein: p.Ala375Val
Coding: c.1124C>T
MANE Select: NM_015533
Type: single nucleotide variant
Location: chr11:61344157 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.40
Residue 375: the dhal domain

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

Similar variants

TKFC p.Arg543Ile Likely pathogenic ★★ same type
TKFC p.Arg228Gln Uncertain significance ★★ ⚠ same type
TKFC p.Asp403Asn Uncertain significance ★★ ⚠ same type
TKFC p.Gln257Pro Uncertain significance ★★ ⚠ same type
TKFC c.194-13C>T Benign ★★ same type
TKFC c.775+39A>C Benign ★★ same type
TKFC p.Ala185Thr Benign ★★ same type
TKFC p.Thr157= Benign ★★ same type

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/tkfc-p-ala375val (accessed [today's date]).

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