Is TTLL5 p.Leu1237Pro (c.3710T>C) pathogenic?

TTLL5 p.Leu1237Pro (c.3710T>C) is classified Uncertain significance in TTLL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-15). AlphaMissense: likely benign (0.1073); Very rare (popmax 0.00195%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TTLL5 p.Leu1237Pro (c.3710T>C)?

TTLL5 p.Leu1237Pro (c.3710T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TTLL5 p.Leu1237Pro (c.3710T>C) in the general population?

TTLL5 p.Leu1237Pro (c.3710T>C) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about TTLL5 p.Leu1237Pro (c.3710T>C)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

TTLL5 p.Leu1237Pro

c.3710T>C · rs1226502037 · VCV1497720

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -6.39	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 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 291 kb · p 0.36 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,180,018 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,614,032 alleles · very rare exomes 22/1,461,874 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,305
Finnishnot grpmax-eligible	0.00156%	64,032

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: TTLL5
Protein: p.Leu1237Pro
Coding: c.3710T>C
MANE Select: NM_015072
dbSNP: rs1226502037
Type: single nucleotide variant
Location: chr14:75882872 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.56 · 1 PDB
Residue 1237: the 'disordered' region

Full TTLL5 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

Similar variants

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TTLL5 p.Ala446Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1023Gln Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1023Trp Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1035Gln Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg111Ser Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1163Trp 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/ttll5-p-leu1237pro (accessed [today's date]).

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