Is CARMIL2 p.Ser425Phe (c.1274C>T) pathogenic?

CARMIL2 p.Ser425Phe (c.1274C>T) is classified Benign in CARMIL2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.2765); Low-frequency (popmax 2.29%, amr).

How common is CARMIL2 p.Ser425Phe (c.1274C>T) in the general population?

CARMIL2 p.Ser425Phe (c.1274C>T) is low-frequency (popmax 2.29%, amr) (gnomAD).

What do computational predictors say about CARMIL2 p.Ser425Phe (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.2765) — an in-silico prediction, not a clinical call.

CARMIL2 p.Ser425Phe

c.1274C>T · rs188574195 · VCV784539

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2765 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.29%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2765	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.26, phastCons 0.96
Regional constraint	o/e 0.97	unconstrained · MANE · 4,899 bp · p 0.31 · regional, not allelic
Overall
CADD	19.0	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 2.29% Admixed American · 1,350/58,898 alleles

Filtering AF 2.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.15%

Overall 0.156% 2,502/1,600,484 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.29%	44
East Asian	1.87%	54
Remaining individualsnot grpmax-eligible	0.258%	388
South Asian	0.1%	997
Ashkenazi Jewishnot grpmax-eligible	0.0409%	2,448
African / African-American	0.0361%	2,772
Middle Eastern	0.0165%	6,044
European (non-Finnish)	0.00255%	39,225

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: CARMIL2
Protein: p.Ser425Phe
Coding: c.1274C>T
MANE Select: NM_001013838
dbSNP: rs188574195
Type: single nucleotide variant
Location: chr16:67648254 (GRCh38)
Gene constraint: LOEUF 0.701 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.50

Full CARMIL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CARMIL2 p.Ser425= Likely benign ★ same residue
CARMIL2 c.1334+1G>T Likely pathogenic ★★ same type
CARMIL2 c.2313+1G>A Likely pathogenic ★★ same type
CARMIL2 c.871+1G>T Pathogenic ★★ same type
CARMIL2 c.958+1G>A Likely pathogenic ★★ same type
CARMIL2 p.Arg174Ter Pathogenic/Likely pathogenic ★★ same type
CARMIL2 p.Asn530Lys Pathogenic/Likely pathogenic ★★ same type
CARMIL2 p.Gln1379Ter 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/carmil2-p-ser425phe (accessed [today's date]).

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