Is IQCE p.Ser374Phe (c.1121C>T) pathogenic?

IQCE p.Ser374Phe (c.1121C>T) is classified Uncertain significance in IQCE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1373); Very rare (popmax 0.00534%, afr).

How common is IQCE p.Ser374Phe (c.1121C>T) in the general population?

IQCE p.Ser374Phe (c.1121C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about IQCE p.Ser374Phe (c.1121C>T)?

AlphaMissense predicts likely benign (score 0.1373) — an in-silico prediction, not a clinical call.

IQCE p.Ser374Phe

c.1121C>T · VCV4276291

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1373 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1373	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.10	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 4.1	GERP 1.5, phastCons 0.29
Regional constraint	o/e 1.15	unconstrained · MANE · 51 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	20.2	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 0.00534% African / African-American · 4/74,952 alleles

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

Overall 0.000248% 4/1,613,872 alleles · very rare exomes 2/1,461,618 · genomes 2/152,254 · 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: IQCE
Protein: p.Ser374Phe
Coding: c.1121C>T
MANE Select: NM_152558
Type: single nucleotide variant
Location: chr7:2589983 (GRCh38)
Gene constraint: LOEUF 1.442 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.36
Residue 374: the 'disordered' region

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

Similar variants

IQCE p.Lys538Arg Uncertain significance ★★ ⚠ same type
IQCE p.Asp645= Benign/Likely benign ★★ same type
IQCE p.Leu277= Benign/Likely benign ★★ same type
IQCE p.Pro586Ser Likely benign ★★ same type
IQCE p.Met1Ile Likely pathogenic ★ same type
IQCE p.Trp498Ter Pathogenic ★ same type
IQCE p.Tyr255Ter Pathogenic ★ same type
IQCE c.1440+1G>T Uncertain significance ★ 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/iqce-p-ser374phe (accessed [today's date]).

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