Is AHSG p.Ser74Pro (c.220T>C) pathogenic?

AHSG p.Ser74Pro (c.220T>C) is classified Uncertain significance in AHSG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-26). AlphaMissense: likely benign (0.1453); Absent from gnomAD v4.1.

How common is AHSG p.Ser74Pro (c.220T>C) in the general population?

AHSG p.Ser74Pro (c.220T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AHSG p.Ser74Pro (c.220T>C)?

AlphaMissense predicts likely benign (score 0.1453) — an in-silico prediction, not a clinical call.

AHSG p.Ser74Pro

c.220T>C · rs2474619571 · VCV2257041

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1453 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1453	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.6	GERP -2.6
Regional constraint	o/e 1.02	unconstrained · MANE · 7,785 bp · p 0.66 · regional, not allelic
Overall
CADD	6.517	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AHSG
Protein: p.Ser74Pro
Coding: c.220T>C
MANE Select: NM_001622
dbSNP: rs2474619571
Type: single nucleotide variant
Location: chr3:186615691 (GRCh38)
Gene constraint: LOEUF 1.042 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.59
Residue 74: the cystatin fetuin-a-type 1 domain

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

Similar variants

AHSG p.Val342Met Uncertain significance ★★ ⚠ same type
AHSG p.Ala170= Benign/Likely benign ★★ same type
AHSG p.Arg317Cys Benign ★★ same type
AHSG p.Met248Thr Benign ★★ same type
AHSG p.Ser256Thr Benign ★★ same type
AHSG p.Thr270= Benign ★★ same type
AHSG p.Val142Leu Benign ★★ same type
AHSG p.Arg317His 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/ahsg-p-ser74pro (accessed [today's date]).

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