Is TYR p.Ser375Phe (c.1124C>T) pathogenic?

TYR p.Ser375Phe (c.1124C>T) is classified Pathogenic in TYR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: likely pathogenic (0.6893); Very rare (popmax 0.0022%, sas).

How common is TYR p.Ser375Phe (c.1124C>T) in the general population?

TYR p.Ser375Phe (c.1124C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about TYR p.Ser375Phe (c.1124C>T)?

AlphaMissense predicts likely pathogenic (score 0.6893) — an in-silico prediction, not a clinical call.

TYR p.Ser375Phe

c.1124C>T · VCV3721081

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6893	likely pathogenic ✓ concordant with ClinVar
REVEL	0.932	strongly pathogenic-leaning
SaProt	LLR -8.41	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 117 kb · p 0.00089 · regional, not allelic
Overall
CADD	29.9	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 0.0022% South Asian · 2/91,072 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,613,544 alleles · very rare exomes 2/1,461,446 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,536
European (non-Finnish)	8.48e-05%	1,179,741

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: TYR
Protein: p.Ser375Phe
Coding: c.1124C>T
MANE Select: NM_000372
Type: single nucleotide variant
Location: chr11:89227910 (GRCh38)
Gene constraint: LOEUF 1.346 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.79 · 1 PDB

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

Similar variants

TYR p.Ser375= Likely benign ★ same residue
TYR c.1036+1G>A Pathogenic/Likely pathogenic ★★ same type
TYR c.1036+2T>G Pathogenic ★★ same type
TYR c.1037-1G>A Pathogenic/Likely pathogenic ★★ same type
TYR c.1037-2A>G Pathogenic/Likely pathogenic ★★ same type
TYR c.1037-3C>G Pathogenic/Likely pathogenic ★★ same type
TYR c.1037-7T>A Pathogenic/Likely pathogenic ★★ same type
TYR c.1185-2A>G Pathogenic/Likely pathogenic ★★ 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/tyr-p-ser375phe (accessed [today's date]).

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