Is TTLL5 p.Pro176Ser (c.526C>T) pathogenic?

TTLL5 p.Pro176Ser (c.526C>T) is classified Uncertain significance in TTLL5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-07). AlphaMissense: likely pathogenic (0.7812); Very rare (popmax 0.00568%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TTLL5 p.Pro176Ser (c.526C>T)?

TTLL5 p.Pro176Ser (c.526C>T) is associated with Inborn genetic diseases, inherited retinal dystrophy (ClinVar).

How common is TTLL5 p.Pro176Ser (c.526C>T) in the general population?

TTLL5 p.Pro176Ser (c.526C>T) is very rare (popmax 0.00568%, nfe) (gnomAD).

What do computational predictors say about TTLL5 p.Pro176Ser (c.526C>T)?

AlphaMissense predicts likely pathogenic (score 0.7812) — an in-silico prediction, not a clinical call.

TTLL5 p.Pro176Ser

c.526C>T · rs146224123 · VCV957456

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00568%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7812	likely pathogenic
REVEL	0.212	benign-leaning
SaProt	LLR -8.69	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 291 kb · p 0.36 · regional, not allelic
Overall
CADD	24.5	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 0.00568% European (non-Finnish) · 67/1,179,906 alleles

Filtering AF 0.00454% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00417%

Overall 0.00459% 74/1,613,744 alleles · very rare exomes 63/1,461,676 · genomes 11/152,068 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00568%	17,611
Remaining individualsnot grpmax-eligible	0.0048%	20,822
Finnishnot grpmax-eligible	0.00469%	21,335
East Asian	0.00223%	44,868

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.Pro176Ser
Coding: c.526C>T
MANE Select: NM_015072
dbSNP: rs146224123
Type: single nucleotide variant
Location: chr14:75699211 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.56 · 1 PDB
Residue 176: the ttl domain

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

Also linked: inherited retinal dystrophy

Similar variants

TTLL5 p.Arg420Ter Pathogenic/Likely pathogenic ★★ same condition
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TTLL5 p.Glu543Lys Pathogenic ★★ ⚠ same condition
TTLL5 p.Ala1042Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Ala328Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Ala446Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1023Gln Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1023Trp 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-pro176ser (accessed [today's date]).

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