Is SPTA1 p.Phe375Ser (c.1124T>C) pathogenic?

SPTA1 p.Phe375Ser (c.1124T>C) is classified Conflicting classifications of pathogenicity in SPTA1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-27). AlphaMissense: likely pathogenic (0.965); Very rare (popmax 0.00534%, afr).

How common is SPTA1 p.Phe375Ser (c.1124T>C) in the general population?

SPTA1 p.Phe375Ser (c.1124T>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about SPTA1 p.Phe375Ser (c.1124T>C)?

AlphaMissense predicts likely pathogenic (score 0.965) — an in-silico prediction, not a clinical call.

SPTA1 p.Phe375Ser

c.1124T>C · rs929328527 · VCV993465

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.965 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.965	likely pathogenic · top 1% in SPTA1
REVEL	0.763	pathogenic-leaning
SaProt	LLR -15.38	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 75 kb · p 2.2e-07 · regional, not allelic
Overall
CADD	25.8	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 0.00534% African / African-American · 4/74,912 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,613,742 alleles · very rare exomes 1/1,461,556 · genomes 3/152,186 · joint denominator

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: SPTA1
Protein: p.Phe375Ser
Coding: c.1124T>C
MANE Select: NM_003126
dbSNP: rs929328527
Type: single nucleotide variant
Location: chr1:158674664 (GRCh38)
Gene constraint: LOEUF 0.591 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 3 PDB

Full SPTA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPTA1 c.1350+1G>C Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.1833+1G>A Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.24+1G>A Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.2464+1G>A Likely pathogenic ★★ same type
SPTA1 c.2806-13T>G Pathogenic/Likely pathogenic ★★ same type
SPTA1 c.2898+2T>C Likely pathogenic ★★ same type
SPTA1 c.390+1G>A Likely pathogenic ★★ same type
SPTA1 c.4339-99C>T 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/spta1-p-phe375ser (accessed [today's date]).

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