Is ALCAM p.Pro194Ser (c.580C>T) pathogenic?

ALCAM p.Pro194Ser (c.580C>T) is classified Uncertain significance in ALCAM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely benign (0.0967); Very rare (popmax 0.00769%, sas).

How common is ALCAM p.Pro194Ser (c.580C>T) in the general population?

ALCAM p.Pro194Ser (c.580C>T) is very rare (popmax 0.00769%, sas) (gnomAD).

What do computational predictors say about ALCAM p.Pro194Ser (c.580C>T)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

ALCAM p.Pro194Ser

c.580C>T · rs761194368 · VCV3108536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00769%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -8.09	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	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 180 kb · p 0.27 · regional, not allelic
Overall
CADD	19.74	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 0.00769% South Asian · 7/91,068 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00255%

Overall 0.000547% 8/1,461,532 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00769%	13,010
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: ALCAM
Protein: p.Pro194Ser
Coding: c.580C>T
MANE Select: NM_001627
dbSNP: rs761194368
Type: single nucleotide variant
Location: chr3:105534695 (GRCh38)
Gene constraint: LOEUF 0.474 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.13 · 1 PDB
Residue 194: a disulfide bond; a turn; the ig-like v-type 2 domain

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

Similar variants

ALCAM p.Asp81= Benign ★★ same type
ALCAM p.His508= Benign/Likely benign ★★ same type
ALCAM p.Leu254= Benign ★★ same type
ALCAM p.Pro84Leu Benign ★★ ⚠ same type
ALCAM p.Ser454= Benign/Likely benign ★★ same type
ALCAM p.Thr301Met Benign ★★ ⚠ same type
ALCAM p.Tyr224= Benign ★★ same type
ALCAM p.Ala19Pro 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/alcam-p-pro194ser (accessed [today's date]).

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