Is AFF4 p.Ser277Thr (c.830G>C) pathogenic?

AFF4 p.Ser277Thr (c.830G>C) is classified Benign/Likely benign in AFF4 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.067); Rare (popmax 0.105%, nfe); Associated with Inborn genetic diseases.

How common is AFF4 p.Ser277Thr (c.830G>C) in the general population?

AFF4 p.Ser277Thr (c.830G>C) is rare (popmax 0.105%, nfe) (gnomAD).

What do computational predictors say about AFF4 p.Ser277Thr (c.830G>C)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

AFF4 p.Ser277Thr

Q: What condition is associated with AFF4 p.Ser277Thr (c.830G>C)?

AFF4 p.Ser277Thr (c.830G>C) is associated with Inborn genetic diseases, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.830G>C · rs141068875 · VCV766774

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -7.90	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 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 36 kb · p 0.00057 · regional, not allelic
Overall
CADD	20.7	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 0.105% European (non-Finnish) · 1,244/1,180,046 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0986%

Overall 0.0818% 1,321/1,614,064 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.105%	949
Ashkenazi Jewishnot grpmax-eligible	0.0912%	1,096
Remaining individualsnot grpmax-eligible	0.0496%	2,016
African / African-American	0.0174%	5,763
Admixed American	0.00667%	14,997
Finnishnot grpmax-eligible	0.00312%	32,015

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: AFF4
Protein: p.Ser277Thr
Coding: c.830G>C
MANE Select: NM_014423
dbSNP: rs141068875
Type: single nucleotide variant
Location: chr5:132934235 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 277: the 'disordered' region

Full AFF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome

Similar variants

AFF4 p.Ser277Ile Uncertain significance ★★ ⚠ same residue
AFF4 p.Arg258Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 p.Met260Val Likely pathogenic ★★ ⚠ same condition
AFF4 p.Pro253Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 p.Thr254Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 c.1133+3A>G Uncertain significance ★★ same condition
AFF4 p.Ala114Thr Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala114Val Uncertain significance ★★ ⚠ same condition

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/aff4-p-ser277thr (accessed [today's date]).

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