Is STRC p.Val1635Phe (c.4903G>T) pathogenic?

STRC p.Val1635Phe (c.4903G>T) is classified Conflicting classifications of pathogenicity in STRC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-19). AlphaMissense: likely benign (0.1596); Rare (popmax 0.136%, sas); Associated with Monogenic hearing loss.

What condition is associated with STRC p.Val1635Phe (c.4903G>T)?

STRC p.Val1635Phe (c.4903G>T) is associated with Monogenic hearing loss (ClinVar).

How common is STRC p.Val1635Phe (c.4903G>T) in the general population?

STRC p.Val1635Phe (c.4903G>T) is rare (popmax 0.136%, sas) (gnomAD).

What do computational predictors say about STRC p.Val1635Phe (c.4903G>T)?

AlphaMissense predicts likely benign (score 0.1596) — an in-silico prediction, not a clinical call.

STRC p.Val1635Phe

c.4903G>T · rs2915791 · VCV227972

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1596 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Monogenic hearing loss

Computational evidence

Protein change
AlphaMissense	0.1596	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -11.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 2, phastCons 0.99
Regional constraint	o/e 0.91	unconstrained · MANE · 649 bp · p 0.42 · regional, not allelic
Overall
CADD	21.9	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 0.136% South Asian · 120/88,514 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.108%

Overall 0.0318% 508/1,598,140 alleles · rare exomes 389/1,446,766 · genomes 119/151,374 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.225%	445
South Asiangrpmax	0.136%	738
African / African-American	0.0428%	2,338
Middle Eastern	0.0333%	3,003
Remaining individualsnot grpmax-eligible	0.0323%	3,101
European (non-Finnish)	0.0277%	3,604
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,855
Admixed American	0.00835%	11,978

Amish 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: STRC
Protein: p.Val1635Phe
Coding: c.4903G>T
MANE Select: NM_153700
dbSNP: rs2915791
Type: single nucleotide variant
Location: chr15:43600624 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.21

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

Disease context

Monogenic hearing loss

Similar variants

STRC p.Val1635Ala Likely benign ★ same residue
STRC c.4219-1G>A Pathogenic/Likely pathogenic ★★ same condition
STRC p.Arg1073Ter Pathogenic ★★ same condition
STRC p.Arg1338Ter Pathogenic/Likely pathogenic ★★ same condition
STRC p.Arg1729Ter Pathogenic ★★ same condition
STRC p.Arg1730Ter Pathogenic/Likely pathogenic ★★ same condition
STRC p.Gln1343Ter Pathogenic/Likely pathogenic ★★ same condition
STRC p.Gln1353Ter Pathogenic ★★ 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/strc-p-val1635phe (accessed [today's date]).

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