Is APCS p.Ser119Phe (c.356C>T) pathogenic?

APCS p.Ser119Phe (c.356C>T) is classified Uncertain significance in APCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: likely pathogenic (0.6214); Ultra-rare (popmax 0.01%, amr).

How common is APCS p.Ser119Phe (c.356C>T) in the general population?

APCS p.Ser119Phe (c.356C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about APCS p.Ser119Phe (c.356C>T)?

AlphaMissense predicts likely pathogenic (score 0.6214) — an in-silico prediction, not a clinical call.

APCS p.Ser119Phe

c.356C>T · VCV3930835

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6214 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6214	likely pathogenic
REVEL	0.296	indeterminate
SaProt	LLR -11.60	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.1, phastCons 0.99
Regional constraint	o/e 1.17	unconstrained · MANE · 783 bp · p 0.0074 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.01% Admixed American · 6/59,990 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00198% 32/1,613,922 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Admixed Americangrpmax	0.01%	9,998
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.00178%	56,190

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: APCS
Protein: p.Ser119Phe
Coding: c.356C>T
MANE Select: NM_001639
Type: single nucleotide variant
Location: chr1:159588392 (GRCh38)
Gene constraint: LOEUF 1.826 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 94.48 · 13 PDB
Residue 119: a turn; the pentraxin (ptx) domain

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

Similar variants

APCS p.Ala146Thr Uncertain significance ★ ⚠ same type
APCS p.Ala58Val Uncertain significance ★ ⚠ same type
APCS p.Arg64His Uncertain significance ★ ⚠ same type
APCS p.Arg86Gly Uncertain significance ★ ⚠ same type
APCS p.Asp203His Uncertain significance ★ ⚠ same type
APCS p.Gln74Glu Uncertain significance ★ ⚠ same type
APCS p.Glu118Lys Uncertain significance ★ ⚠ same type
APCS p.Ile113Asn 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/apcs-p-ser119phe (accessed [today's date]).

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